Chronic liver disease is characterised by the gradual destruction of liver tissue over time, whereby healthy and regenerating liver tissue is slowly replaced with scar and necrotic tissue. This is known as liver cirrhosis. Normal liver function is impaired and the scar tissue progressively diminishes blood flow through the liver. As normal regenerating liver tissue is lost, nutrients, hormones, drugs and toxins are no longer effectively processed.
This can result in symptoms including abnormal clearance of proteins absorbed through the intestinal tract, leading to accumulation of ammonia; abnormal excretion, leading to an accumulation of bilirubin in the blood, producing jaundice; increased sinusoidal pressure, leading to fluid accumulation in the abdomen (ascites); and portal hypertension (and portosystemic shunting) wherein scarred liver tissue acts as a barrier to blood flow, leading to increased portal blood pressure and oesophageal varices.
Patients with chronic liver disease can be in a fairly stable clinical state and exhibit few or no symptoms. However, such patients are at risk of an abrupt deterioration in their condition which can lead to acute-on-chronic liver failure. This transition from a “compensated” state, where the liver is able to function, albeit at a reduced level, to a “decompensated” state, where liver function fails, involves the effect of precipitating events. Precipitating events associated with chronic liver disease include gastrointestinal bleeding, infection (sepsis), portal vein thrombosis and dehydration.
For example, 50% of patients with cirrhosis of the liver have oesophageal varices and in a third of these patients, the oesophageal varices will burst and cause gastrointestinal bleeding within two years of diagnosis (Grace N D (1992) Gastroenterol Clin North Am 21: 149-161). An upper gastrointestinal bleed is known to increase the susceptibility to life-threatening complications such as bacterial peritonitis, sepsis, renal failure and hepatic encephalopathy (Teran et al. (1997) Gastroenterology 112: 473-482; Garden et al. (1985) Br J Surg 72: 91-95; Pauwels et al. (1996) Hepatology 24: 802-806; Bleichner et al. (1986) Br J Surg 73: 724-726) resulting in the death of about 30% of patients despite adequate control of bleeding (Grace 1992 supra).
Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder that occurs in diverse clinical situations such as acute or chronic liver disease and spontaneous portosystemic venous shunting. In the early stages of hepatic encephalopathy subtle mental changes occur such as poor concentration, confusion and disorientation. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling (cerebral edema) and death. In the case of patients who develop HE as a result of chronic liver disease, the onset of HE is often the result of a clinically precipitating event such as gastrointestinal bleeding, sepsis (infection), portal vein thrombosis or dehydration.
Gastrointestinal bleeding and portosystemic shunting allows toxic substances, which are usually metabolised by the liver, to bypass the liver, enter the systemic circulation and cross the blood-brain barrier to exert direct or indirect neurotoxic effects on the central nervous system. Ammonia accumulation is thought to play an important role in the progression of hepatic encephalopathy and multiorgan failure (respiratory failure, cardiovascular failure, kidney failure). In addition to ammonia, septicaemia (or bacterial peritonitis) which develops soon after a gastrointestinal bleed is also likely to be a contributing factor to hepatic encephalopathy.
Liver decompensation can then lead to multiorgan failure and hepatic encephalopathy. In the early stages of hepatic encephalopathy subtle mental changes such as poor concentration or the inability to construct simple objects occurs. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death.
The prognosis for patients with chronic liver disease is difficult to estimate because the condition has many causes. Preventative measures to minimise progression from the compensated state to the decompensated state include avoidance of further causative agents which will worsen the condition, such as complete abstinence from alcohol and vaccination against hepatitis A and B.
However, once liver decompensation occurs, the chances of survival are reduced and liver transplantation is the only treatment that can extend life. Since it is liver decompensation that leads to a reduced life expectancy, it is highly desirable to prevent liver decompensation from occurring.
A common therapy for patients with hepatic encephalopathy involves strategies to reduce the concentration of ammonia. These include restriction of dietary protein intake; administration of lactulose, neomycin, L-ornithine L-aspartate (LOLA), or sodium benzoate; and cleansing enemas.